β-Elemene Attenuates Fibrosis after Esophageal Endoscopic Submucosal Dissection via Modulating the HIF-1α/HK2/p38-MAPK Signaling Axis

Abstract

Esophageal fibrosis and stricture after endoscopic submucosal dissection (ESD) are serious postoperative complications. Previous evidence has highlighted an anticancer role of β-elemene in esophageal squamous cell carcinoma. This study put forward a hypothesis on the inhibitory effect of β-elemene on esophageal fibrosis after ESD and aimed to elaborate the underlying mechanisms. Our initial network pharmacology analyses determined hypoxia-inducible factor-1alpha (HIF-1α), hexokinase 2 (HK2), and p38MAPK in association with the effect of β-elemene. We validated that the levels of HIF-1α, HK2, and p-p38MAPK were elevated in esophageal granulation tissue after ESD and corresponding fibroblasts. Esophageal fibroblasts were treated with β-elemene of gradient concentrations. The results indicated that β-elemene repressed the proliferation of esophageal fibroblasts and the levels of fibrosis-related factors. Further, β-elemene inhibited HIF-1α expression leading to restricted proliferation and augmented apoptosis of fibroblasts. HIF-1α induced p38MAPK phosphorylation by activating the HK2 transcription and consequently accelerated fibroblast proliferation. Together, β-elemene diminished HIF-1α expression and impaired the HK2-mediated p38MAPK phosphorylation, thereby repressing the esophageal fibrosis.

β-Elemene Attenuates Renal Fibrosis in the Unilateral Ureteral Obstruction Model by Inhibition of STAT3 and Smad3 Signaling via Suppressing MyD88 Expression

“…Hong et al demonstrated that β-elemene ameliorates esophageal fibrosis by reducing the expression of α-SMA, collagen I, and fibronectin [ 39 ]. We demonstrated that β-elemene similarly ameliorated renal tubular injury and fibrosis in the UUO model.…”

Combined transcriptome and proteome analysis of yak PASMCs under hypoxic and normoxic conditions

“…The up-regulation of HK under hypoxia enhances glycolysis, autophagy and epithelial-mesenchymal transformation ( Chen et al, 2018 ). The up-regulation of hexokinase can promote glycolysis by binding to the mitochondrial outer membrane and providing ATP for cell metabolism ( Hong et al, 2021 ). LDH can be divided into LDHA and LDHB subtypes.…”

β-elemene alleviates esophageal fibrosis after endoscopic submucosal dissection via the FAP-mediated PTEN-PI3K/AKT signaling pathway

“…Furthermore, it has the potential to function as a nano-delivery drug to counteract tamoxifen-induced immunosuppression and thereby enhance chemoimmunotherapy [ 20 ]. Interestingly, β-elemene has been demonstrated to possess the efficacy of mitigating fibrosis in various tissues and organs, including esophageal fibrosis [ [21] , [22] , [23] , [24] ]. However, its specific mechanism in esophageal fibrosis remains unclear.…”